PT2328593E - Cardioplegic preparation - Google Patents

Cardioplegic preparation Download PDF

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PT2328593E
PT2328593E PT97364855T PT09736485T PT2328593E PT 2328593 E PT2328593 E PT 2328593E PT 97364855 T PT97364855 T PT 97364855T PT 09736485 T PT09736485 T PT 09736485T PT 2328593 E PT2328593 E PT 2328593E
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european patent
cardioplegic
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PT97364855T
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Erich Gygax
Thierry Carrel
Hendrik Tevaearai
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Universität Bern
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

DESCRigÄODESCRIPTION

PREPARAgÄO CARDIOPLÉGICACARDIOPLEGIC PREPARATION

Campo da Invengao A invengao refere-se a cirurgia cardiaca. Mais precisamente, refere-se a uma preparagäo cardioplégica que pode ser utilizada durante a cirurgia cardiaca.Field of the Invention The invention relates to cardiac surgery. More precisely, it refers to a cardioplegic preparation that can be used during cardiac surgery.

Estado da técnica Várias técnicas tém sido utilizadas em cenários clínicos para parar e proteger o coragao, e, subsequentemente, permitir a operagáo sobre e no coragao. Embora o potássio e o frió sejam consideradas abordagens padráo para atingir esse objectivo, várias implementagoes foram propostas ao longo das últimas décadas. Curiosamente, no entanto, nenhuma abordagem única foi aceite por unanimidade pela comunidade de cirurgiöes cardíacos e, embora a cirurgia cardíaca seja considerada hoje como muito mais segura do que algumas décadas atrás, todas as técnicas de cardioplegia apresentam desvantagens. Na verdade, embora estratégias cardioplégicas sejam usadas para proteger o miocárdio durante os procedimentos de coragao aberto, pode-se aínda considerar que o tecido cardíaco aínda sofre de isquemia, bem como de lesoes por reperfusáo.Several techniques have been used in clinical settings to stop and protect the heart, and thereafter allow operation over and over the crown. Although potassium and cold are considered standard approaches to achieve this goal, several implementations have been proposed over the past decades. Interestingly, however, no single approach was unanimously accepted by the community of cardiac surgeons, and although cardiac surgery is now considered as much safer than a few decades ago, all cardioplegia techniques have drawbacks. Indeed, although cardioplegic strategies are used to protect the myocardium during open-heart procedures, cardiac tissue may still be considered to suffer from ischemia, as well as reperfusion injury.

Descrigao da invengao A invengäo refere-se a uma dose de uma preparagáo cardioplégica que contém, pelo menos, magnésio e potássio, e, mais precisamente, a uma dose como definido ñas reivindicagöes .Description of the Invention The invention relates to a dose of a cardioplegic preparation containing at least magnesium and potassium, and more precisely at a dose as defined in the claims.

De um modo vantajoso, a preparagäo é inicialmente feita de duas solugöes separadas, a primeira contendo o referido magnésio e a segunda contendo um anestésico local, por exemplo, a procaina. As duas solugöes contém os seguintes componentes:Advantageously, the preparation is initially made of two separate solutions, the first containing said magnesium and the second containing a local anesthetic, for example procaine. The two solutions contain the following components:

As solugöes säo tamponados de modo a que o pH após mistura de ambas as solugöes é entre 5,5 e 7,0.The solutions are buffered so that the pH after mixing of both solutions is between 5.5 and 7.0.

Vantajosamente, sao usadas as moléculas seguintes:Advantageously, the following molecules are used:

As variagöes podem incluir o seguinte componente adicional: - AdenosinaVariations may include the following additional component: - Adenosine

Outras variagöes também podem usar: - Em vez de procaina, xilocaina e/ou novocaína e/ou qualquer outro anestésico local compatível com os componentes utilizados na preparagäo - Em vez de xilitol, manitol e/ou qualquer tipo de agúcar compatível com os outros componentes utilizados na preparagäo - Cloreto de magnésio em vez de sulfato de magnésio.Other variations may also use: - Instead of procaine, xylocaine and / or novocaine and / or any other local anesthetic compatible with the components used in the preparation - Instead of xylitol, mannitol and / or any type of sugar compatible with the other components used in the preparation - Magnesium chloride instead of magnesium sulphate.

Mais específicamente, a dose de acordo com a invengäo é definida como a seguir:More specifically, the dose according to the invention is defined as follows:

A água é utilizada para ter urn volume final (solugäo A + solugäo B) de 20 a 250 mL. A solugäo A é tamponada com ácido cítrico mono-hidratado a um pH de 5,5 a 7,0.The water is used to have a final volume (solution A + solution B) of 20 to 250 ml. Solution A is buffered with citric acid monohydrate at a pH of 5.5 to 7.0.

Numa forma de realizagäo preferida, a dose é definida como a seguir :In a preferred embodiment, the dose is defined as follows:

0 pH da solugäo misturada pronta a usar é 6,0. A preparagäo é hiperosmolar com urna osmolaridade da solugäo misturada pronta a usar de aproximadamente 850 mosmol/L.The pH of the ready-to-use blended solution is 6.0. The preparation is hyperosmolar with an osmolality of the ready-to-use blended solution of approximately 850 mosmol / L.

Ensaios farmacológicos Vários ensaios farmacológicos foram realizados e conduzem á preparagäo de acordo com a invengáo. Depois de várias tentativas sem sucesso, tornou-se possivel obter urna preparagäo que é estável e estéril ao longo de vários meses. Além disso, a preparagäo de acordo com a invengáo oferece a vantagem de evitar a conhecida incompatibilidade entre a procaina e o sulfato. Significativamente, os testes também demonstraram que a 2-8 °C e durante os primeiros 60 minutos após a mistura das solugoes A e B, esta incompatibilidade nao é relevante.Pharmacological tests Various pharmacological tests have been carried out and lead to the preparation according to the invention. After several unsuccessful attempts, it has become possible to obtain a preparation that is stable and sterile over several months. In addition, the preparation according to the invention offers the advantage of avoiding the known incompatibility between procaine and sulfate. Significantly, tests have also shown that at 2-8 ° C and during the first 60 minutes after mixing of solutes A and B, this incompatibility is not relevant.

Em comparagáo com as solugoes cardioplégicas anteriores, a preparagäo de acordo com a invengáo tem urna concentragäo de potássio mais elevada. Ensaios experimentáis e clínicos confirmaram urna biodisponibilidade reduzida de ioes de potássio quando em presenga de xilitol e/ou ácido cítrico. Desse modo, ao aumentar o teor inicial de potássio na solugäo cardioplégica, é garantida a concentragäo necessária para se conseguir o efeito cardioplégico. Além disso, ensaios clínicos confirmaram que nenhuma sobredosagem de potássio é alcangada.Compared with the above cardioplegic solutions, the preparation according to the invention has a higher potassium concentration. Experimental and clinical trials have confirmed a reduced bioavailability of potassium ions when in the presence of xylitol and / or citric acid. Thus, by increasing the initial potassium content in the cardioplegic solution, the concentration required to achieve the cardioplegic effect is guaranteed. In addition, clinical trials have confirmed that no overdose of potassium is reached.

Em comparagáo com as solugoes cardioplégicas anteriores, o pH é também reduzido para 6,0, o que, curiosamente e vantajosamente, permite aumentar o efeito da procaina.Compared with the above cardioplegic solutions, the pH is also reduced to 6.0, which, curiously and advantageously, increases the effect of procaine.

Produgäo A solugäo A é preparada de urna forma estéril e armazenada num frasco de 95 mL. A solugäo B é também preparada de urna forma estéril e armazenada separadamente numa seringa de 5 mL protegida da luz.Produgation Solution A is prepared in a sterile form and stored in a 95 ml vial. Solution B is also prepared in a sterile form and stored separately in a 5 ml light-protected syringe.

Ambiente cirúrgicoSurgical environment

Pelo menos 3-4 horas antes do procedimento cirúrgico, as solugoes sao armazenadas a 2-8 °C. A solugäo pronta a usar (100 mi) é obtida por injecgao do conteúdo da seringa (solugäo B, 5 mL) no frasco (solugäo A, 95 mL) . Esta mistura resultante é administrada no prazo de 60 minutos após a mistura, de preferencia no prazo de 15 minutos após a mistura.At least 3-4 hours before the surgical procedure, the solutes are stored at 2-8 ° C. The ready-to-use solution (100 ml) is obtained by injecting the syringe contents (solution B, 5 ml) into the vial (solution A, 95 ml). This resulting mixture is administered within 60 minutes after mixing, preferably within 15 minutes after mixing.

Ensaios clínicos A preparagäo de acordo com a invengäo foi testada em vários doentes. A combinagao dos compostos foi aínda testada em mais de 3.000 doentes e mostrou claras vantagens em relagao as solugoes cardioplégicas tradicionais. Nao só a administragao é simplificada, mas a parada cardíaca é guase instantánea, permitindo, desse modo, gue o cirurgiáo imediatamente concentre-se no seu procedimento cirúrgico. De facto, na maioria das outras estratégias cardioplégicas, o cirurgiáo tem administrar urna guantidade muito maior de solugäo e esperar até 5 minutos até gue o coragäo seja considerado pronto para ser operado. Além disso, a solugäo actual permite a parada e a protecgäo normalmente durante mais de 45-60 minutos, ao passo gue outras solugoes tradicionalmente necessitam de ser repetidas a cada 20 minutos. Os resultados clínicos sáo significativamente superiores, urna vez gue várias das complicagoes pós-operatórias podem ser reduzidas, tal como a taxa de arritmias cardíacas pós-operatórias. Acima de tudo, a preparagäo de acordo com a invengäo pode ser integrada no conceito de novas máquinas de circulagáo extracorpórea (ECC, Extra Corporeal Circulation) destinadas a reduzir ou eliminar o trauma de tais dispositivos. Isto foi confirmado recentemente num estudo mostrou, em particular, urna redugáo significativa de reacgoes inflamatorias pós-ECC.Clinical trials The preparation according to the invention has been tested in several patients. The combination of the compounds was further tested in more than 3,000 patients and showed clear advantages over traditional cardioplegic solutions. Not only is administration simplified, but cardiac arrest is instantaneous, thus allowing the surgeon to immediately focus on his or her surgical procedure. In fact, in most other cardioplegic strategies, the surgeon has to administer a much larger amount of solution and wait up to 5 minutes until the heart is considered ready for surgery. In addition, the current solution allows stopping and protection normally for more than 45-60 minutes, while other solutes traditionally need to be repeated every 20 minutes. The clinical results are significantly higher, since several of the postoperative complications can be reduced, such as the rate of postoperative cardiac arrhythmias. Above all, the preparation according to the invention can be integrated into the concept of new Extracorporeal Circulation (ECC) machines intended to reduce or eliminate the trauma of such devices. This has been recently confirmed in one study showing, in particular, a significant reduction of post-CCA inflammatory reactions.

Observou-se uma redugäo significativa do nivel de enzimas cardiacas no pós-operatório. Isso confirma uma melhor protecgäo do miocárdio.There was a significant reduction in the level of cardiac enzymes in the postoperative period. This confirms better protection of the myocardium.

Vantagens proporcionadas pela invengäoAdvantages provided by the invention

Em comparagäo com outras solugoes cardioplégicas do estado da técnica, a preparagäo cardioplégica de acordo com a invengäo apresenta várias vantagens significativas, em particular: 1. A apresentagäo com duas solugoes separadas permite evitar as consequéncias da incompatibilidade conhecida entre o sulfato e a procaina. 2. A mistura das duas solugoes de 2 a 8 °C permite evitar a formagao anormal de microparticulas dentro de pelo menos uma hora. 3. A produgäo pode ser realizada á temperatura ambiente antes da esterilizagao. Ambas as solugoes podem entäo ser consideradas estáveis durante mais de 9 meses á temperatura ambiente. Isto pode ser considerado uma vantagem significativa uma vez que a produgäo pode ser ampliada e os produtos podem ser armazenados e toda a logística é facilitada. 4. A injecgäo imediata da preparagäo recém-misturada ñas artérias coronárias permite uma parada cardíaca imediata. 5. Pelo facto da solugäo ser concentrada num volume baixo (apenas 100 mL), evita-se a hemodiluigäo. 6. O efeito cardioplégico é prolongado e normalmente mantido por pelo menos 60 minutos. 7. A administragäo é simplificada uma vez que a preparagäo pode ser directa e rápidamente injectada dentro da aorta pelo próprio cirurgiäo. 8. A preparagáo é particularmente adaptada para operagöes de revascularizagao do miocárdio. Vários estudos foram realizados em hospitals. Estes estudos incluiram milhares de doentes. Todos confirmaram que pode ser alcangada urna protecgáo significativamente melhor do miocárdio. Na verdade, a experiencia mostra que o nivel de enzimas cardiacas no pós-operatório, em outras palavras, marcadores de lesoes cardiacas celulares, é reduzido em comparagáo com outras solugoes cardioplégicas.In comparison with other cardioplegic solutions of the prior art, the cardioplegic preparation according to the invention has several significant advantages, in particular: 1. The presentation with two separate solutes allows to avoid the consequences of the known incompatibility between the sulphate and the procaine. 2. The mixing of the two solutes at 2 to 8 ° C allows to avoid the abnormal formation of microparticles within at least one hour. 3. The production can be carried out at room temperature prior to sterilization. Both solutions can then be considered stable for more than 9 months at room temperature. This can be considered a significant advantage since the production can be expanded and the products can be stored and all the logistics are facilitated. 4. Immediate injection of freshly mixed preparation into the coronary arteries allows immediate cardiac arrest. 5. Because the solution is concentrated to a low volume (only 100 ml), hemodilution is avoided. 6. The cardioplegic effect is prolonged and usually maintained for at least 60 minutes. 7. The administration is simplified since the preparation can be directly and quickly injected into the aorta by the surgeon himself. 8. The preparation is particularly suited for myocardial revascularization operations. Several studies were conducted in hospitals. These studies included thousands of patients. All have confirmed that significantly better protection of the myocardium can be achieved. In fact, experience shows that the level of cardiac enzymes in the postoperative period, in other words, markers of cellular cardiac lesions, is reduced in comparison with other cardioplegic solubilities.

Lisboa, 23 de Margo de 2015.Lisbon, March 23, 2015.

Claims (2)

REIVINDICALES 1. Dose de uma preparagäo cardioplégica que compreende:A dose of cardioplegic preparation comprising: em que o volume final da referida dose é entre 20 e 250 mL e em que a solugáo A é tamponada com ácido cítrico mono-hidratado a um pH de 5,5 a 7,0 .wherein the final volume of said dose is between 20 and 250 ml and wherein solution A is buffered with citric acid monohydrate at a pH of 5.5 to 7.0. 2. Dose de uma reparagáo cardioplégica de acordo com a reivindicagáo 1, em que é utilizada a seguinte preparagäo:The dose of a cardioplegic repair according to claim 1, wherein the following preparation is used: Lisboa, 23 de Margo de 2015. Et«-öj3öafi ?aterii,£iiiji»Lisbon, March 23, 2015. Et «-oj3öafi? Aterii, £ iiiji» &quot;iERMANV Questions about this communication ? Grssfilfer, Philippe ame mmm m, \ Ghentm dss GHarmsttes S: P.O. Box 5107 tost: Laudarme SUISSE&quot; iERMANV Questions about this communication? Grssfilfer, Philippe ame mmm, \ Ghentm dss GHarmsttes S: P.O. Box 5107 tost: Laudarme SUISSE Decision to grant a European patent pursuant to Article 97(1) EFC ÄiaÄg eXáminátíOfi: ,of Euro pean psídht Applíéattpn No. Ö97S5455 j ä: .EdfppsÄ patent: vÄthe: title anp the supperting documents ihdipited in Ée cgmoianiestien pursuant ta: Rule 71¾ IPi dated :£&amp;.&amp;7,14 is hereby granted In rsspsefcofthe designated Oontraeting Statesv Patent No. ‘ 232859:3 Date af filing : 1Ö.08.ÖS Priority claimed : lidöÄSW aftd :Rröp:rleiö:Fie) X AT BE B# GH CY GZ DE DK EE ES Fl: FftlGBYSR HR HU ÍE IS IT L! LT LU LV MG MK MT NL NO PL FT RO SE SI SK SM TR Universität Bern Vdrwdlty RfsdireMion Hochschulstrasse 4 3012 Bern-OH This decision will take effect on the date on which the European Patent Bulletin mentions the grant (Art 97p) EPC). The mention .oflthe grant «ill foe pufefeheáin European Patent Bulletin i®1: of 3T. 12x14, Examining; Diytsipn Uryga*PölQwy V Zimmer B Y.entunni F(1) EFC äiaÄg eXáminátíOfi: of Euro pean psídht Applíéattpn No. Ö97S5455 j ä: .EdfppsÄ patent: vÄthe: title anp the supperting documents ihdipited in Ege cgmoianiestien pursuant ta: Rule 71¾ IPi dated: £ & 7,14 is hereby granted In rsspsefcofthe designated Oontraeting Statesv Patent No. '232859: 3 Date af filing: 1Ö.08.ÖS Priority claimed: lidöÄSW aftd: Rröp: rleiö: Fie) X AT BE B # GH CY GZ DE DK EE ES Fl: FftlGBYSR HR HU ÍE IS IT L! LT LU LV MG MK MT NL NO PL FT RO SE SI SK SM TR Universität Bern Vdrwdlty RfsdireMion Hochschulstrasse 4 3012 Bern-OH This decision will take effect on the date on which the European Patent Bulletin mentions the grant (Art 97p) EPC). The mention of the grant was made in the European Patent Bulletin of 1T. 12x14, Examining; Diytsipn Uryga * PölQwy V Zimmer B Y.entunni F Registered letter to EPO postal service: 28.11.14 SPG ForMSOQSA: fö:S7 (¿7/1 !/1«) ^Λ^£ίϊΚϋίϊ0·,Μβ.·ε»Τ«βΗΒ0ϋΝ&lt;3 OBER DIE ERTEIl»©: : EINES EUROPÄISCHEN PATENTS {EPA Form 2006) EPA Informritionsbroschüre &quot;Nationales Recht /um EPÜ&quot; Ösess: Srpschöre gqfMii: nfKziiähe: IbÍQrfnptiónen:AU de rt fwiaien Erfordernissen und ιφπ Handiungeh, dfoNof den PA¡®dt|^Sb{#Í5: de¡ Weitragas-tsA*®} vorzuRehmen árnclí ^;F^W®ria--5!fe?«0!sSfe^eii::?í&gt;:-«fl95geJi.. Oa diese. Handlnngeneinem: ständigst! Wandet unterworfen aitid, sollte irrifner nur dt® netteste Ausgabe der Broschüre Tianutzt werden. Nachträgliche ieformationafiwerd*3.n im Ärnisbiatt veröffentlicht, Übersetzung der europäischen Patentschrift nacft Artikel 65 (1) des Europäischen Patento he rot n ko m men s Sie werden frnwjy darauf hnqeviosen ci^ss» bestimmte Veitrags&amp;ti^en n«mb Artp©i Fi (1) E0U eure toerretzimf der aurgpäisoheri h'ibtötuf wird in Seif MíHéilt^g gemiß(δ) ÍsPC^veh#teé¥hic DifoNfehteinteichung tofoser Öbefsefäöhg karm ¿ur ÄigS' haben; dass äa.®.: fPidteatt: irtTeife·!« StsaiÄö dsn beitóífeódah Staaten; ate SoOiAniang aft nicht éingetrefen gilt Weitere Si^síheÉsiis-.tíBíteéíttBéhi. Ütüe Zahlung von «Jahresgeböhren für europäische Pafenie Nach Artikel· T4:l· ß:PU können ''it®foífo!é(' Jahröagebföhfgbiiteir das: eütöpäisötiö Ρθί0η|®Γΰ®ίJahre: feritobsift werde», die an Jss #hr ähdöblfoifoh. iti dein der HinWeisi abTdfe Bheifoftf: &amp;s:tóuf0pteifohéh Patéíiísiirti ’EöropAischsn RafentbiätN .fesfesftn^éiHisíbM'iWíitl. Weitere Éíífíelhdt^hi:éntói?f^eh Sie Mié der ii^híggháftHfeniás^c^íír'S; ...........................................................................:.....NÖTE EßiAIINC: TCANS ίΕ0!®!0Ν':ΐΒι©ΗΑ!ίίΤ:'Α................................................................................................ EÜRÖPEAN RÄTENT pTO Form 20:06) EPü Information Brochure '‘National law relating to the EPC&quot; This brochure provides useful infemration regmdiiig formal requirements^ and the steps'|ó :.fesfoi«i:#¡é? Contracting States in order to acquire rights in those states. Since the necessary steps are subject to change the latest edition of the broCh!#di^bdidiNWSyis be «¡sed! Subsequent iriföf fofofoft ía:pfeblisitodiIn the· Ófíisiáídöiirhai, Translation of the European patent application under Article &amp;5{1) of the European Patent Convention Your .-attention:· is again drawn to te requirements regarding translation of the European patent specification laid down by a number of Contracting States binder Ar‘eto 66(1) 6KT to which reference &gt;s mace in the communication under Role 71(5) EPC Failure to supply such tranatehonfo) may result in fite patent being deemed to be void &quot;ab initio’1 in the Stotefe) tn question. For further details you are ......-(»eönimüiiideilitöi^en&amp;iRiffte abossünsntoned fewicfaurs;· Payment of renews! feses tor European patents Under Article 141 EPC &quot;national&quot; renewal fees In respect of a European patent may be imposed for the years Which follow that in Which the mention of the grant of the European patent is published in the &quot;European Patent Bulletin-' For further details you are recommended to epSstilHite qbqyfoméftt:i^ REMARQUE: REMTIWEIÁ.LAOEÖiSfÖN &quot;DÉ 2EUVRANCE tf UN BREVET :Ε0Ν0ΕΕΕ:ΝΙ{0:Ερ:fö iSOüSJ Brochure d'inf»rmation de )’OE8 ‘Oroft national reiatlf á la CBE“ Öbtfe: brochure: teustofodfoiSfes: mnsel^RentontSi SU:!' tos opnditiöns: dé {ofme fpí|píses et ;:Ádr IPS actos :a gCiy»hj?!ift aúprés óficsá: dp brevet des Elate oOntraefänts aux tins cfobtenir des droits dans íes Etats contractants. Etans dormé que Íes actas indispensables sont ;suseeptibíasda rttodifeaii&amp;nfo ΐίspfdÁ befo:de to¡ Fours oghsplter ia demísre edition de läibroöhdifo: Tome fofbrfoÄiT au dpurnatöffieifii;. Traduction du fascicule da brevet européen en vertu de ¡‘article 65(1} de ia Convention sur le brevet européen Yottó étténtíhnéstiiferfeüyéau afffeéfesutfó certains EíiAs con&amp;iaplapts,. en vertu de ÍArtfofo |S:(1j QBE,, da fourhir :pf?á n aductor du fascicule du brevet auropssn a laqi telle if eel fait reference Ü3.1S Is notification stab ie so ifcr nément a la regie 71 (5) COE Si la(!eS) tfädüötiönfoj nfostfns sönt) p,qb:foörri(e(.sj, le: brevet purepéen psuf, des I'otlgihej sire reputó Pads foffet üehs ce:t(bés) Etat(s):; P&amp;ur plus ife i#íail% nöus vöus férivpybnS: a te brochdreAusmenifoprtpsY Paiement des taxes annuelies pour le brevet européen Cpnfpridémént Altórtiote 141 CB:É dasiaxés shnMeifoéThatlenáiep&quot; düée:su:®ré.ckt fcrsv&gt;-í eurepeer: pqüvehfM&amp;. :pérgués:ppar Ιρΐ): ánhéés suivant eelie -m ttotirs m· leatieiíe:· te: meatisn de ia deiívtancs du: brevetiSirapeeti est iptiblié aa &quot;SidJeBn eufQpian.jdés: brévets, Fteur plus dé. Éiétails:- nous vóus renvóyens ä fa ibrochure susmenifohnee.Registered letter to EPO postal service: 28.11.14 SPG ForMSOQSA: fö: S7 (7/1! / 1 «) ^ Λ ^ £ ίϊΚϋίϊ0 ·, Μβ. Ε» Τ «βΗΒ0ϋΝ <3 OBER DIE ERTEIl» ©: EINES EUROPÄISCHEN PATENTS {EPA Form 2006) EPA Informritionsbroschüre &quot; Nationales Recht / um EPÜ &quot; Ösess: Srpschöre gqfMii: nfKziiähe: IbiQrfnptionen: rt fwienien Erfordernissen und ιφπ Handiungeh, dfoNof denAtDr ^ The composition of the present invention may be prepared by the following methods: Handlnngeneinem: ständigst! Wandet unterworfen aitid, sollte irrifner nur dt® netteste Ausgabe der Broschüre Tianutzt werden. Nachträgliche ieformationafiwerd * 3.n im Ärnisbiatt veröffentlicht, Übersetzung der europäischen Patentschrift nacft Artikel 65 (1) des Europäischen Patents he rot n ko m men s Sie werden frnwjy darauf hnqeviosen ci ss' bestimmte Veitrags & (1) E0U eure toerretzimf der aurgpäisoheri h'ibtötuf wird in Seif MíHéilt ^ g gemiß (δ) ÍsPC ^ teé ¥ hic DifoNfehteinteichung tofoser Öbefsefäöhg karm ¿ur ÄigS 'haben; dass äa.®: fPidteatt: irtTeife ·! StsaiÄö dsn beitóífeódah Staaten; to SoOiAniang aft nicht éingetrefen gilt Weitere Si ^ séheisiis-.tíBíteéíttBéhi. Tüe Z von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von von Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z.. Z................................................................................................................................................................................ ΡίίJJ...................... iti dein der HinWeisi abTdfe Bheifoftf: &amp; s: t0f0pteifohéh Patéiísisiirti 'EöropAischsn RafentbiätN .FocusHisíbM'iWíitl Weitere Éífifilédt ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ .................................................. ...................: ..... NÖTE EßiAIINC: TCANS ίΕ0! ®! 0Ν ': ΐΒι © ΗΑ! ΊίΤ:' Α ...... .................................................. ........................................ EÜRÖPEAN RÄTENT pTO Form 20:06) EPü Information Brochure '' National law relating to the EPC &quot; This brochure provides useful information on the formal requirements and the steps taken to ensure the success of the project. Contracting States in order to acquire rights in those states. Since the necessary steps are subject to change the latest edition of the BroCh! # Di ^ bdidiNWSyis be "thirst! Subsequent to the patent application, the European patent application under Article 5 (1) of the European Patent Convention, is hereby amended to read as follows: by a number of Contracting States binder Ar'eto 66 (1) 6KT to which reference> mace in the communication under Role 71 (5) EPC Failure to supply such tranatehonfo) may result in fite patent being deemed void &quot; ab initio'1 in the Stotefe) tn question. For further details you are .......... - ('eonimüiiideilitöi ^ in & Riffte abossünsntoned fewicfaurs; · Payment of renewals! European patents under Article 141 EPC &quot; renewal fees In respect of a European patent may be imposed For further details, please refer to the European Patent Bulletin. For further details, please refer to the European Patent Bulletin. For further details, please refer to the European Patent Bulletin. A BREVET: Ε0Ν0ΕΕΕ: ΝΙ 0 0 0 0 0 Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Bro Oro Oro Oro Oro Oro Oro; - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Etans slept for the first time, and it was important to note that it was not necessary to take the necessary steps to carry out the work of the Committee on the Elimination of All Forms of Discrimination. Traduction du fascicule de brevet européen en vertu de l'article 65 (1) de la Convention sur le brevet européen Yottó étténtíhnéstiiferfeüyéau afffeéfesutfó certains EíiAs with & iaplapts, in the vertu of Art. (5) COE If the (s) (s) (s) of the information provided by the Commission shall be notified to the Commission, (s), (b), (c), (b), (c), (b), (b), and (b). annuelies pour le brevet européen Cpnfpridémént Alttertiote 141 CB: It is deiaxés shnMeifoéThatlenáiep &quot; düée: su: è.ckt fcrsv &gt; -e eurepeer: pqüvehfM &amp;.: pérgués: ppar Ιρΐ): ánhéés suivant eelie -m ttotirs m · leatieiíe: · te : meatisn de ia deiívtancs du: brevetiSirapeeti est iptiblié aa &quot; SidJeBn eu fQpian.jdés: brévets, Fteur plus dé. Éiétails: - nous vôus renvóyens ä fa ibrochure susmenifohnee.
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